Colon targeted delivery systems have been the subject of much research because the colon is a site for some specific diseases, such as, for example, ulcerative colitis, Crohn's disease, bowel cancer, infections and constipation and the like, which require local delivery of the drug(s) for treatment thereof. In particular, 5-amino-salicylic acid (mesalamine or 5-ASA) has been used for many years for the treatment of colonic disorders. When administered orally, mesalamine is mostly absorbed in the small intestine before reaching the colon.
In order to deliver a drug such as mesalamine to the colon selectively, a pharmaceutical composition is required to meet the following criteria: (1) the composition is not degraded or disintegrated in the upper GI tract; (2) the composition does not release the drug in the upper GI tract; (3) the composition releases the drug effectively in the colon; and (4) the composition is easy to formulate in a form suitable for loading the drug. Further, the composition preferably must be easily processed for manufacture. Various approaches have been used for oral delivery of drug(s) to the colon. These include time-dependent delivery, pH-dependent systems and delivery systems that utilize bacteria in the colon or enzymes produced by these bacteria to affect drug release.
Time release systems have been developed, such as Pulsincap® and Time Clock®, which involve a polymeric coating of a certain thickness that dissolves over time, and an outer coating that does not dissolve in the acidic environment of the stomach. This approach assumes that, while transit time is highly variable in the stomach, transit time through the small intestines is relatively constant. See Chourasia, Pharmaceutical Approaches to Colon Targeted Drug Delivery Systems, J. Pharma. Sci. 6(1): 33-66 (2003).
Saffran et al., Science, 233, pp. 1081-84 (1988) reported the use of azopolymers (i.e. polymers cross-linked with azo-aromatic groups) for colonic delivery. These are degraded by colonic bacterial azo-reductases, but are unaffected by gastric enzymes, and therefore were proposed as potential coatings for colonic delivery systems. These coatings are not ideal for a colon targeted delivery system, since release of drug depends on the presence of colonic anaerobic bacteria. Since the flora of anaerobic bacteria in the colon is variable, these polymers provide inconsistent drug delivery to the colon. Also, the safety of these polymeric coating materials is not completely established.
Site-specific delivery into the colon can also be achieved by the use of coating materials that are specifically degraded in the colonic environment by the action of microorganisms and/or the reductive environment found there. Such materials include but are not limited to azopolymers (Saffren et al., Science, pp. 1081-84 (1988)), amylose (Milojevic et al., Proc. Int. Symp. Contr. Rel. Bioact. Mater., 20, 288, 1993), calcium pectinate (Rubenstein et al., Pharm. Res., 10, 258-263, 1993), chondroitin sulphate (Rubenstein et al., Pharm. Res., 9, 276-278, 1992), and modified guar gum (Rubenstein and Gliko-Kabir, S. T. P. Pharma Sciences 5, 4146, 1995).
Predominantly, colonic delivery has been achieved for many years by the use of pH-sensitive coatings. By raising the threshold pH at which dissolution of the coating begins, it is possible to achieve colon-specific delivery by the use of pH sensitive polymers.
The most commonly used pH-dependent coating polymers are methacrylic acid copolymers e.g., Eudragit® L100-55, Eudragit® L100 and Eudragit® S100, which dissolve at pH 5.5, 6.0 and 7.0, respectively. Eudragit® L100 and S100 are copolymers of methacrylic acid and methyl methacrylate, respectively. The ratio of free carboxyl groups to ester groups is approximately 1:1 in Eudragit® L100 and 1:2 in Eudragit® S 100.
The pH-dependent systems exploit the generally accepted view that pH of the human gastrointestinal (GI) tract increases progressively from the stomach (pH 1-3) to the small intestine (pH 5-7) to the colon (pH 7-8). See Ashford, et al., Journal of Drug Targeting 2, pp. 241-58 (1994). Taking advantage of the highest pH value of the colon, the dosage form containing the active drug in a core is coated with pH-dependent material, which dissolves at the pH of the colon.
U.S. Pat. Nos. 5,541,171 and 5,541,170 describe an orally administered composition containing mesalamine and coated with a methacrylic acid copolymer that only dissolves in colonic-intestinal juices above a pH of 7 (Eudragit® S100). But it has been reported that, because the colonic pH of certain patients fails to reach a pH of 7 or because of a fast transit time in certain patients, embodiments of these patents fail to dissolve completely in the GI tract, with patients observing intact tablets in their stools. See, e.g., Schroeder et al., New Eng. J. Med. 317, 1625-29 (1987); Ashford et al., Int. J. Pharm, 91, pp. 241-245 (1993).
The present inventors have found a system that does not degrade, disintegrate or release the drug, e.g., mesalamine, in the upper GI tract, but instead releases it in the ileum and colon. Moreover, it is easy to formulate and easy to manufacture. In addition, the system developed is a delayed release composition, which slowly releases drug in aqueous media having a pH 6.5 to 6.8, and which quickly releases drug in media having a pH of 7.0 or more. More specifically, using the present invention in the three stage dissolution test discussed hereinbelow, about 10% to about 60%, and more preferably about 20% to about 50%, of the drug by weight is released at a residence time of about 2 hours at a pH of 6.8, while at a pH of less than 6.5, the drug is released slowly, if at all, at a rate of less than about 20% by weight during the same residence time, while at a pH of 7.2 or more, the drug is released very rapidly (greater than about 80% by weight) at a residence time of 2 hours.